Animal studies show that some aminoalkylester and amide prodrugs of racemic ibuprofen and naproxen, in particular some N-(3-diethylaminopropyl)amides, exhibit analgesic and antiinflammatory activity significantly better than the parent compounds, even though “in vitro” they have been found to be poor inhibitors of the synthesis of prostaglandins. All these prodrugs, except a glycine amide, have also been found to be significantly less irritating to the gastric mucosa than their precursor free acids. (Shanbhag V R et al., J. Pharm. Sci., 81, 149, 1992 and references 8-19) therein cited.
Piketoprofen [(±)2-(3-benzoylphenyl)-N-(4-methyl-2-pyridinyl)propionamide] and Amtolmetin Guacil (also named guaiacol ester of tolmetinglycinamide, Eufans) are further examples of non steroidal antiinflammatory (NSAI) prodrugs in current therapeutic use. Moderate antiinflammatory activity, minor side effects and good gastro-intestinal tolerance are reported for a series or N-[2-(1-piperidinyl)propyl]amides of some NSAI drugs such as racemic ibuprofen, indomethacin, p-chlorobenzoic acid, acetylsalicyclic acid, diacetylgentisic acid and adamantane-1-carboxylic acid (Nawladonski F. and Reewuski, Pol. J. Chem., 52, 1805, 1978). Other amides of racemic 2-arylpropionic acids have been disclosed by S. Biniecki et al., [PL 114050 (31. 01. 1981)], H. Akguen et al., [Arzneim-Forsch., 46, 891, 1986] and by G. L. Levitt et al., [Russ. J. Org. Chem., 34, 346, 1998].
Anti-inflammatory and analgesic potencies “in vivo”, comparable and sometimes greater than those of the precursor free acids, along with decreased number of gastric lesions, have been reported for some N-3-[(1-piperidinyl)propyl]amides of racemic ketoprofen and flurbiprofen and for certain Mannich bases obtained reacting their amides with formaldehyde and secondary amines such as morpholine, piperidine, dicyclohexylamine, dimethylamine, diethylamine, dibenzylamine and dibutylamine (N. Kawathekar et al., Indian J. Pharm. Sci., 60, 346, 1998).
International patent application, WO 00/40088, has recently reported that the mere conversion to an amide derivative of a 2-arylacetic and/or 2-arylpropionic acid is enough to change a selective COX-1 inhibitor into a COX-2 selective inhibitor which explains the decreased gastrolesivity of said amides, for a long time believed to be only NSAI prodrugs.
In the past, inhibition of the cyclooxygenase enzymes was known to be proper of the S enantiomer of 2-arylpropionic acids alone, joined together with the portion of R CoA-thioester suffering bioconversion “in vivo”. Therefore, the poor correlation between enzymatic inhibition “in vitro” and analgesic effects “in vivo” found for certain R,S 2-arylpropionic acids (Brune K. et al., Experientia, 47, 257, 1991) has induced to presume that alternative mechanisms, such as inhibition of transcription of the kB-nuclear transcription factor (NF-kB) and/or inhibition of neutrophil chemotaxis induced by interleukin 8 (IL-8), can be operating.
R enantiomers of flurbiprofen, ketoprofen, naproxen, thiaprofen and phenoprofen are, in fact, disclosed in WO 00/40088 as inhibitors of the NF-kB transcription factor activation and claimed to be useful in the treatment of NF-kB dependent diseases (asthma, tumor, shock, Crohn'disease and ulcerative colitis, arteriosclerosis, etc).
IL-8 is an important mediator of inflammation and has been shown to be a potent chemotactic/cell activator for polymorphonucleate neutrophils and basophils (PMNs), and T lymphocytes. Cellular sources of IL-8 include monocytes, PMNs, endotelial cells, epithelial cells, and keratinocytes when stimulated by factors such as lipopolysaccaride, IL-1 and TNF-α. On the other hand, the complement fragment C5a, in addition to being a direct mediator of inflammation, has been found to induce both IL-8 synthesis and high level of IL-8 release from monocytes. The quantity of IL-8 recovered from C5a activated monocytes in peripheral blood mononuclear cells is up to 1,000 fold greater than that released from comparable numbers of PMNs under similar conditions. Therefore IL-8 released from C5a-activated monocytes may play a significant role in expanding and prolonging cellular infiltration and activation at the sites of infection, inflammation, or tissue injury (Ember J. A. et al., Am. J. Pathol., 144, 393, 1994).
In response to immunologic and infective events, activation of the complement system mediates amplification of inflammatory response both via direct membrane action and via release of a series of peptide fragments, generally known as anaphylatoxins, generated by enzymatic cleavage of the C3, C4 and C5 complement fractions. These peptides include C3a, C4a, both made of 77 aminoacids; in turn, C5 convertase cleaves the C5 complement fraction to give the glycoprotein C5a of 74 aminoacids.
Anaphilatoxins contribute to the spreading of the inflammatory process by interaction with individual cell components; their common properties are cellular release of vasoactive amines and lysosomal enzymes, contraction of smooth muscle and increased vascular permeability. Moreover, C5a causes chemotaxis and aggregation of neutrophils, stimulates the release of leukotrienes and of oxidized oxygen species, induces the transcription of IL-1 in macrophages and the production of antibodies.
The C5a peptide fragment of the complement has been defined as the “complete” pro-inflammatory mediator. On the contrary, other inflammatory mediators such as selected cytokines (IL-8, MCP-1 and RANTES, for example) are highly selective towards self-attracted cells, while histamine and bradykinin are only weak chemotactic agents.
Convincing evidences support the involvement of C5a, “in vivo”, in several pathological conditions including ischemia/reperfusion, autoimmune dermatitis, membrane-proliferative idiopathic glomerulonephritis, airway iperresponsiveness and chronic inflammatory diseases, ARDS and COPD, Alzheimer'disease, juvenile rheumatoid arthritis (N. P. Gerard, Ann. Rev. Immunol., 12, 755, 1994).
In view of the neuro-inflammatory potential of C5a/C5a-desArg generated by both local complement production and amyloid activation joined with astrocyte and microglia chemotaxis and activation directly induced by C5a, complement inhibitors have been proposed for the treatment of neurological diseases such as Alzheimer'disease (McGeer & McGeer P. L., Drugs, 55, 738, 1998).
Therefore, the control of the local synthesis of complement fractions is considered of high therapeutic potential in the treatment of shock and in the prevention of rejection (multiple organ failure and hyperacute graft rejection) (Issekutz A. C. et al., Int. J. Immunopharmacol, 12, 1, 1990; Inagi R. et at., Immunol. Lett., 27, 49, 1991). More recently, inhibition of complement fractions has been reported to be involved in the prevention of native and transplanted kidney injuries taking account of complement involvement in the pathogenesis of both chronic interstitial and acute glomerular renal injuries. (Sheerin N. S. & Sacks S. H., Curr. Opinion Nephrol. Hypert., 7, 395, 1998).
Genetic engineering and molecular biology studies led to the cloning of complement receptors (CRs) and to the production of CRs agonists and antagonists. The recombinant soluble receptor CR1 (sCR1), that blocks enzymes activating C3 and C5, has been identified as a potential agent for the suppression of C activation on ischemia/reperfusion injury (Weisman H. F. et al., Science, 239, 146, 1990; Pemberton M. et al., J. Immunol., 150, 5104, 1993).
The cyclic peptide F-[OPdChWR], is reported to antagonize the C5a binding to its CD38 receptor on PMNs and to inhibit C5a-dependent chemotaxis and cytokine production by macrophages and rat neutropenia induced by C5a and LPS stimulation (Short A. et al., Br. J. Pharmacol., 126, 551, 1999; Haynes D. R. et al., Biochem. Pharmacol., 60, 729, 2000). Both C5aR antagonist CGS 27913 and its dimer CGS 32359 are reported to inhibit, “in vitro”, C5a binding to neutrophil membranes, intracellular Ca2+ mobilization, lysozyme release, neutrophil chemotaxis and dermal edema in rabbits (Pellas T. C. et al., J. Immunol., 160, 5616, 1998).
Finally, selection from phage libraries with the “phage display” technique has led to the isolation of a specific C5aR antagonist able to decrease inflammatory responses in diseases mediated by immuno-complexes and in ischemia and reperfusion injuries (Heller T. et al., J. Immunol., 163, 985, 1999).
Despite their therapeutic potential, only two of the above discussed C5a antagonists have demonstrated activity “in vivo”; furthermore, their use is therapeutically limited by their peptidic nature. (Pellas T. C., Wennogle P., Curr. Pharm. Des., 10, 737, 1999).
Characteristic neutrophil accumulation can be observed in some pathologic conditions, for example in the highly inflamed and therapeutically recalcitrant areas of psoriatic lesions. Neutrophils are chemotactically attracted and activated by the sinergistic action of chemokines, IL-8 and Gro-a released by the stimulated keratinocytes, and of the C5a/C5a-desArg fraction produced via the alternative complement pathway activation (T. Terui et al., Exp. Dermatol., 9, 1, 2000). In many circustances it is, therefore, highly desirable to combine inhibition of the chemotaxis induced by C5a and inhibition of the chemotaxis induced by IL-8 in one single agent.
Non-peptidic antagonists of complement fractions have also been prepared, for example substituted-4,6-diamino-quinolines. In particular, [N,N″-bis-(4-amino-2-methyl-6-quinolyl)]urea and [6-N-2-chlorocynnamoyl)-4,6-diamino-2-methylquinoline] have been found selective C5R antagonists, their IC50 ranging between 3.3 and 12 μg/mL (Lanza T. J. et al., J. Med. Chem., 35, 252, 1992).
Some serine-protease inhibitors [nafamostat mesilate (FUT 175) and certain analogs] have been recently reported to be inhibitors of both complement activation and C3a/C5a production (Ueda N. et al., Inflammation Res. 49, 42, 2000).
U.S. Pat. No. 6,069,172 reports the use of pharmaceutical formulations of R(−)ketoprofen ammonium salts for the inhibition of neutrophil chemotaxis induced by IL-8.
WO 00/24710 discloses N-acylsulfonamides of R(−)2-aryl-propionic acids as inhibitors of IL-8 dependent polymorphonucleate leukocytes chemotaxis.
Two recent patent applications [WO 01/58852 and WO 01/79189] disclose certain R-2-aryl-propionamides and R-2-(aminophenyl)propionamides useful for preventing leukocyte activation induced by IL-8.
We have recently observed that the mere formal reduction of the hetero-aromatic ring of certain R 2-aryl-N-(pyridinyl)propionamides causes marked loss of potency (1 or 2 logarithmic order) in the capacity to inhibit PMN neutrophil chemotaxis induced by IL-8. Unexpectedly, the related R 2-aryl-N-(piperidinyl)propionamides have been found to be potent inhibitors of chemotaxis of human PMN leukocytes and monocytes induced by the C5a fraction of the complement.
These unexpected findings have originated a novel family of omega-aminoalkylamides of R-2-aryl-propionic acids which are able to inhibit the chemotactic activity induced by C5a and other chemotactic proteins whose biological activity is associated with activation of a 7-membered-domain receptor (7-TD) homologous to the receptor of C5a (for example, the C3a receptor and the CXCR2 receptor; Neote K. et al., Cell, 72, 415, 1993; Tometta M. A., J. Immunol., 158, 5277, 1997).